Expression of Iron Transporters and Pathological Hallmarks of Parkinson’s and Alzheimer’s Diseases in the Brain of Young, Adult, and Aged Rats

Lü, Lina; Qian, Zhong Ming; Wu, Kaijin; Yung, Wing‐Ho; Ke, Ya

doi:10.1007/s12035-016-0067-0

Cited by 73 publications

(63 citation statements)

References 71 publications

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“…At present, information on the mechanisms involved in iron transport and homeostasis in oligodendrocytes and microglia remains very limited as compared to neurons and astrocytes. In addition, how the expression of iron transport proteins is controlled in the brain under physiological conditions, and the genetic and non‐genetic causes that might lead to misregulation of brain iron metabolism are two key questions that have yet to be answered. A number of studies have provided evidence for the existence of hepcidin in the brain (Wang et al ., ; Wang et al, ; Raha‐Chowdhury et al, ; Pellegrino et al, ; Lu et al, ; Puy et al, ; Vela, ; Wang et al, ). Recent studies have shown that this iron regulatory hormone is also a central player in brain iron homeostasis and has a key role in controlling iron transport in the BBB, and iron uptake and release in astrocytes and neuronal cells (Du et al, , ; Gong et al, ).…”

Section: Discussionmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 99%

Brain iron transport

Qian

2019

Biological Reviews

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“…Thereafter, a wide‐spread distribution of hepcidin mRNA was also demonstrated in the brains of male Sprague‐Dawley (SD) rats and 9‐week‐old BALB/c mice . In the cerebral cortex, hippocampus, and striatum of mice and SD rats, hepcidin mRNA levels were found to increase with age. The increased hepcidin mRNA and/or protein expression was also observed in the cortex and substantia nigra of SD rats, in the choroid plexus of C57BL/6 mice and Wistar rats, in primary rat astrocytes and microglia cultures and brain tissue of male Wistar rats, after treatment with lipopolysaccharide (LPS) or turpentine oil, and also in the cortex, hippocampus, and striatum in a middle cerebral artery occlusion rat model, as well as in the mouse brain following systemic Escherichia coli infection .…”

Section: Hepcidin and The Treatment Of Neurodegenerative Disordersmentioning

confidence: 76%

“…They also showed that hepcidin protein can be detected in both neurons and glial filbrillary acidic protein (GFAP)‐positive glial cells. Thereafter, a wide‐spread distribution of hepcidin mRNA was also demonstrated in the brains of male Sprague‐Dawley (SD) rats and 9‐week‐old BALB/c mice . In the cerebral cortex, hippocampus, and striatum of mice and SD rats, hepcidin mRNA levels were found to increase with age.…”

Section: Hepcidin and The Treatment Of Neurodegenerative Disordersmentioning

confidence: 97%

Hepcidin and its therapeutic potential in neurodegenerative disorders

Qian

2019

Medicinal Research Reviews

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Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron‐related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood‐brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron‐associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

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“…Interestingly, also the concentration of iron in the brain increases with age (Acosta-Cabronero et al, 2016; Pirpamer et al, 2016). A recent study has demonstrated an age-induced increase in the expression of both divalent metal transporter (DMT1) and α-syn in mice cells (Lu et al, 2016). This result describes a cellular scenario in which the cytoplasmic amount of both divalent metal ions and α-syn increase with age.…”

Section: Role Of Metals In Synucleinopathiesmentioning

confidence: 99%

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

Toni¹,

Massimino

Mario

et al. 2017

Front. Neurosci.

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Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and on low intake of meat, could play a preventive or delaying role in prion and prion-like neurodegenerative diseases. In this review, metal role in the onset of prion and prion-like diseases is dealt with from a nutritional, cellular, and molecular point of view.

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Expression of Iron Transporters and Pathological Hallmarks of Parkinson’s and Alzheimer’s Diseases in the Brain of Young, Adult, and Aged Rats

Cited by 73 publications

References 71 publications

Brain iron transport

Brain iron transport

Hepcidin and its therapeutic potential in neurodegenerative disorders

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

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